Parasitic helminths infect billions of people and animals worldwide. Although drugs are available to treat many infections, the drugs used for treatment of human helminth parasites are expensive and often not distributed to the areas of the world with the most infections, and evidence in agriculturally important animals has indicated that the parasites have developed resistance to many classes of drugs. Additionally, vaccine development has been slow. Helminth parasites have differing mechanisms of reproduction and location of infection in the hosts;however, the immune responses of the hosts to the worm infection are remarkably similar. To address the problem of parasitism and effectively develop treatments, we need a greater understanding of the immune response to the invading parasite. This proposal has three primary objectives: 1) compare the published quantitative trait loci (QTL) regions for helminth parasite resistance and immune responses from human, mouse, sheep and cow using comparative genomics to identify chromosomal regions for fine mapping, 2) identify candidate genes using molecular genetic (QTL fine-mapping) and functional genomic approaches (microarrays and cytokine production), and 3) utilize an effective vaccination method to determine candidate genes related to susceptibility and resistance to internal parasite infections with a functional genomic approach. Preliminary data from comparative genomics indicates that a QTL on Chr 1 of the mouse overlaps with QTL in the other species and will be a primary target of analysis. The three objectives have a collective goal of identifying potential candidate genes involved in the immune response that leads to resistance to parasite infections. The identification of the genes involved in the immune response and resistance can enhance the development of new drugs or vaccines. The understanding of genes involved in the immune response and parasite resistance may lead to the development of new drugs or vaccines. The development of low-cost, effective treatments can improve the health of individuals in many underdeveloped regions of the world.